Relieving constipation with non-ionic surface active agents



United States Patent 3,152,043 RELEEVING CQNSTIPATIUN WlTH NQN-ltlNlC SURFACE ACTIVE AGENTS Wolife Harry Feinstone, Indianapolis, ind, assigner, by mesne assignments, to Paul B. Eider Company, Bryan, Ohio, a corporation of Ghio No Drawing. Filed Apr. 15, 1957, Ser. No. 65$,tl39

6 Claims. (Cl. 16756) This invention relates to a method of relieving constipation by the softening of fecal matter.

Constipation is generally accompanied by the formation of hard, impacted fecal matter, in the distal colon and rectum, which resists elimination. Upon forceable elimination, there is often accompanying pain and traumatic damage to the anal and peri-anal tissues. Upon frequent recurrence of episodes of constipation with attending actuation to straining, there may follow aggravation or partial causation of such conditions as aneurysm, hernia, hemorrhoids and other rectal diseases, and other diseases in which the force of straining causes dilation of injured tissues.

It is desirable also to avoid constipation which aggravates such conditions as dropsy, nephritis and internal congestions. Constipation frequently follows surgery, even when the surgery is unrelated to the gastro-intestinal tract. It is particularly important to avoid straining in the attempt of the patient to have a bowel movement following a surgical operation, because such straining may tear freshly joined tissue.

The previously known cathartics, purgau'ves, laxatives or evacuents induce defecation, in general, by one of the following mechanisms:

(a) Distention of the intestinal canal (e.g., saline cathartics, which increase bulk by osmotic attraction of large amounts of fluid; hydrophilic colloids; indigestible fibers, etc.);

(b) Irritation of the small or large intestine (e.g., emodin and other anthraquinone cathartics-cascara sagrada, aloe, etc.; resinous catharticsjalap, etc.; irritant oils-castor oil, croton oil; and others such as phenolphthalein and calomel);

(c) Emollient cathartics (e.g., liquid petrolatum and vegetable oils).

The irritant cathartics stimulate propulsive movements in the large bowel or throughout the gastro-intestinal tract, depending upon the site of action of a particular drug. This effect is due to an irritant action and may aggravate or produce dangerous effects when used in the presence of abdominal inflammatory conditions such as peritonitis, appendicitis, gastro-enteritis and intestinal obstruction or intussusception. Nor should they be employed during pregnancy or menstruation since the hyperemia they induce may cause abortion or excessive menstrual flow.

Self-medication with the irritant cathartics by uninformed persons in the presence of some of the abovenamed conditions has often led to serious damage and even fatalities.

The saline and other bulk producing cathartics often cause uncomfortable distention, interfere with appetite or induce objectionable diarrhea. The distention of the intestines effected by the saline cathartics is undesirable in certain abdominal diseases that may coexist or during pregnancy or menstruation when congestion of the pelvic organs may lead to abortion or excessive flow.

Perhaps the most objectionable feature of this group of cathartics is the habituation they induce through a reflex dependence upon abnormal distention of the colon and rectum before the bowel is stimulated to empty. This cathartic habit often becomes a diflicult therapeutic problem in itself in addition to the mechanical damage Patented Get. 6, 1964 that may be done to persons with coexistent contraindicating diseases.

The emollient or lubricating cathartics are widely used and have fewer objectionable features than most other classes of cathartics. The chief substances in this category of cathartics are mineral oil and, to a lesser extent vegetable oils, and they act as mechanical lubricants to the degree that they escape saponification and absorption from the intestinal tract. However, it has been found that mineral oil interferes with absorption of carotene, the vitamin A precursor and perhaps other essential nutrients. It has been shown also that a suflicient quantity of the emulsified oils may enter the circulation to cause respiratory complications and other hazards which have led to requirements for warnings against protracted use of petrolatum preparations, particularly in infants and children. A further objection to lubricant oil cathartics is their likelihood to leak insensibly from the anus.

It has been proposed to use dioctyl sodium sulfosuccinate (Aerosol GT.) in the treatment of severe fecal impaction (Wilson and Dickinson, I.A.M.A, 158:261, May 28, 1955). This apparently has produced excellent results in many cases. However, dioctyl sodium succinate is an anionic material, which is affected by the gastrointestinal tracts electrolyte content and pH, which, as is well known, vary greatly. Thus, dioctyl sodium suceinate becomes rapidly unstable in acid environments below pH 2 and in alkaline environments above pH 9. Its solubility decreases with increasing amounts of electrolyte, being less than 1% in water containing only .25 part by weight of NaCl. At higher concentrations of electrolytes, its solubility drops off steeply, thus inhibiting and finally destroying its surface acting and wetting power.

One of the objects of this invention is to provide a uniformly effective method of softening feces, whereby relatively normal bowel movements are induced, with the passing of soft, well-formed stools, without interfering with the normal peristaltic movement of the intestinal tract and without the griping or diarrhea produced by the usual laxative drugs.

Other objects will become apparent to those skilled in the art in the light of the following description.

In accordance with this invention, generally stated, a benign, non-ionic surface active agent is administered internally in relatively substantial doses. The preferred agent is polyoxyethylene (20) sorbitan mono-oleate, also known as polysorbate (USP). This may be administered as a solution or colloidal dispersion in water or a flavored aqueous vehicle; in tablet form by adsorbing the material on a pharmacologically inert base such as milk sugar or silicic acid and by adding other suitable pharmaceutical diluents, which can then be compressed into tablet form; in a gelatin capsule of the hard shell type containing the material triturated onto suitable pharmaceutical diluents, or in a soft gelatin capsule in which the material is contained alone or together with suitable diluents. In each of these dosage forms, the unit quantity of surface active agent per tablet, per capsule or per teaspoonful or other unit quantity of fiuid, may be in the range of five to five hundred milligrams of the material.

The following are examples of particular formulations of actual dosage forms:

Example I Polysorbate 80 (U.S.P.) grams 5046.5 Methylparaben (preservative) do 45.0 Propylparaben (preservative) do 15 Sorbitol (70%) gallons l0 Granulated Sugar lbs Deionized Water (or potable water) gallons to 40 To 15 gallons water, add the sugar and heat and stir to solution. Cool to about 60 C. and add the Methyl- 3 paraben and Propylparaben and finally the Polysorbate 80. Stir to homogeneity. Add and mix the Sorbitol. Cool and make up to final volume of 40 gallons with water. Distribute to package units.

The above preparation is suitable for use in infant formulas or in fruit juices or water in quantities of about 0.6 cc. as the unitdose. Each 0.6 cc. of above preparation will contain 20 mg. of Polysorbate-80.

Thedilution and flavoring agents may of course be varied, by using any of those customarily employed in pharmaceutical preparations and consistent with the uses to which the product is directed.

Example I! ?olysorbate-80 grams 5000 Silicic Acid, special bulky (Mallinckrodt) lbs 8.8 Pharmaceutical colors:

F D & C Red #1 grams 0.6

F D & C Blue #1 do 0.6

Sugar orange (Eaton Clarke Co.) do 1.2 Powdered Sugar lbs 44 Terra Alba lbs 22 Granulated Sugar lbs 9.5 Pharmaceutical lubricants:

Jaguar A-20-B Gum (Stein-Hall Co.) lbs 3.3

Solka Floc BW-lOO (Brown Co.) lbs 1.65

Talc q.s. ad 105.714 lbs.

Dissolve /2 of the colors in 30 cc. water and add and mix into the Polysrbate80. Triturate the colored Polysorbate-80 with the Silicic Acid until free from lumps and color is uniformly distributed. Combine and mix the Powdered Sugar and Terra Alba. Granulate the mixture with a syrup made by dissolving the Granulated Sugar in 10 pints of hot water into which the remainder of the colors are dissolved. Dry in pharmaceutical drying oven to a Weight of 75.6 lbs. Combine the Silicic Acid-Polysorbate-80 mixture with the above dried granulation. Compress into slugs. Reduce slugs to a suitable granulation for compressing into tablets. Lubricate this granulation with the Jaguar A20B, Solka Floc BWlOO and finally add sumcient Talc to bring to a total weight of 105.714 lbs. Compress into /8 tablets each to weigh 7.4 grains (479.5 mg).

The above preparation is suitable for a tablet dosage form. Each tablet will contain 50 mg. of Polysorbate-80 (U.S.P.). However, other procedures, pharmaceutical diluents, colors, etc., may be selected as is known to those skilled in the preparation of tablet dosage forms.

Example III A suitable mix of Silicic Acid triturated with the proper quantity of Polysorbate-SO (e.g., 4 parts Silicic Acid to 5 parts Polysorbate-SO) and diluted with powdered milk sugar or other pharmaceutical diluent may be filled into hard shell capsules by the usual procedures.

Example IV Soft shell capsules may be prepared by making a soft mass of Polysorbate-80 with vegetable oil or water and the usual pharmaceutical diluents employed in the filling of soft gelatin capsules.

The use of polyoxyethylene 40 stearate, another benign, non-ionic surface active agent, is illustrated by the following examples:

Example V Polyoxyethylene 40 stearate (Polyoxyl 40 stearate,

U.S.P.) L grams 5046.5 Methylparaben (preservative) do 45.0 Propylparaben (preservative) do 15 Sorbitol (70%) gallons Granulated Sugar lbs 125 Deionized Water (or potable water), to 40 gallons.

The process of formulation is the same as that of Example I.

4 Example VI Polyoxyethylene 4O stearate grams 5000 Silicic Acid, special bulky (Mallinckrodt) lbs 8.8 Pharmaceutical colors:

F D & C Red #1 grams 0.6

F D & C Blue #1 do 0.6

Sugar Orange (Eaton Clarke Co.) do 1.2 Powdered Sugar lbs 44 Terra Alba lbs 22 Granulated Sugar lbs 9.5 Pharmaceutical lubricants:

Jaguar A-20-B Gum (Stein-Hall Co.) lbs 3.3

Solka Floc BW-lOO (Brown Co.) lbs 1.65 Talc q.s. ad 105.714 lbs.

The process of formulation is the same as that of Example 11.

Example VII Four parts of silicic acid are triturated with five parts of Polyoxyethylene 40 stearate, and diluted with powdered milk sugar or other pharmaceutical diluent to make 20 mg. of Polyoxyethylene 40 stearate per capsule when filled into hard shelled capsules.

Example VIII Soft shelled capsules are filled with a soft mass of Polyoxyethylene 40 stearate in vegetable oil and the usual pharmaceutical diluents to provide a dosage per capsule of 20 mg. of Polyoxyethylene 40 stearate.

A daily dosage of 6.0 cc. of the liquid of Example I or V, or two tablets of Example 11 or VI, or an equivalent dosage of the capsules of Examples III, IV, VII and VIII has been found satisfactory for adults. As little as 0.6 cc. of the liquid of Example I has been found safely effective for infants, for example from 1 to 4 years old.

It has been found that the therapeutic effect of the benign, non-ionic surface active agents such as Polysorbate-SO is gradual, requiring forty-eight to seventy-two hours to induce the initial relief. Thereafter, relatively normal bowel movements can be maintained on continuous dosage until the causative features of the constipation have either been eliminated or the constipation has been supplanted by normal bowel habits.

The Polysorbate-SO is innocuous in the doses required to produce the stool softening effect and such dosage may be maintained over long periods of time without risk or danger. The non-ionic character of an agent such as Polysorbate-SO minimizes variations in its efficacy in difierent individuals, since Polysorbate is soluble and active even in 5% sulfuric acid solution.

Other benign, non-ionic surface active agents may be used, such, for example, as sorbitan monolaurate, sorbitan mono-oleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate and polyoxyethylene sorbitan dilaurate.

Having thus described the invention, what is claimed and desired to be secured by Letters Patent is:

1. The method of softening impacted fecal matter within the intestines of a living human being, comprising introducing into said fecal matter per 0s, a dosage of polyoxyethylene (20) sorbitan mono-oleate in an amount between 5 and 500 milligrams, suificient to effect substantial softening of the matter.

2. The method of softening impacted fecal matter within the intestines of a living human being, comprising introducing into said fecal matter per 0s, a dosage of polyoxyethylene (40) stearate in an amount between 5 and 500 milligrams, suificient to effect substantial softening of the matter.

3. The method of softening impacted fecal matter within the intestines of a living human being, comprising introducing into said fecal matter per 0s a dosage containing between 5 and 500 milligrams of benign, nonionic surface active agent taken from the class consisting of polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (40) stearate, sorbitan mono-laurate, sorbitan mono-oleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate and polyoxyethylene sorbitan dilaurate.

4. The method of softening impacted fecal matter Within the intestines of a living human being, comprising in troducing into said fecal matter per s a dosage of benign, non-ionic surface active higher fatty acid ester of sorbitan in an amount of between and 500 milligrams, sufficient to effect substantial softening of the matter.

5. The method of softening impacted fecal matter within the intestines of a living human being, comprising introducing into said fecal matter per 0s a dosage containing between and 500 milligrams of polyoxyethylene sorbitan monoleate.

6. The method of softening impacted fecal matter within the intestines of a living human being, comprising 6 benign, non-ionic, surface active, polyoxyethylene sorbitan higher fatty acid ester condensation product in an amount between 10 and 500 milligrams, sufficient to effect substantial softening of the matter.

References Cited in the file of this patent UNITED STATES PATENTS Huggins May 31, 1960 OTHER REFERENCES Modern Drug Encyclopedia, 5th Edition, 1952, p. 610.

Am. J. Pharm., December 1949, p. 491.

Sherbet: ].A.M.A., vol. 152, pp. 682686.

Wilson: J.A.M.A., vol. 158, No. 4, May 28, 1955, pp. 261-263.

De Navarre: Am. Perf. and Essen. Oil Review, vol. 64, No. 1, p. 13.

Squibb: Abst. Bull, v01. 25, No. 5, Jan. 30, 1952, p.

introducing into said fecal matter per 0s, a dosage of a A418- 

1. THE METHOD OF SOFTENING IMPACTED FECAL MATTER WITHIN THE INTESTINES OF A LIVING HUMAN BEING, COMPRISING INTRODUCING INTO SAID FECAL MATTER PER OS, A DOSAGE OF POLYOXYETHYLENE (20) SORBITAN MONO-OLEATE IN AN AMOUNT BETWEEN 5 AND 500 MILLIGRAMS, SUFFICIENT TO EFFECT SUBSTANTIAL SOFTENING OF THE MATTER. 